Pharmacoproteomic approach to the study of drug mode of action, toxicity, and resistance: applications in diabetes and cancer.

Proteomics is a powerful technique for investigating protein expression profiles in biological systems and their modifications in response to stimuli or to particular physiological or pathophysiological conditions. It is therefore a technique of choice for the study of drug mode of action, side-effects, toxicity and resistance. It is also a valuable approach for the discovery of new drug targets. All these proteomic applications to pharmacological issues may be called pharmacoproteomics. The pharmacoproteomic approach could be particularly useful for the identification of molecular alterations implicated in type 2 diabetes and for further characterization of existing or new drugs. In oncology, proteomics is widely used for the identification of tumour-specific protein markers, and pharmacoproteomics is used for the evaluation of chemotherapy, particularly for the characterization of drug-resistance mechanisms. The large amount of data generated by pharmacoproteomic screening requires the use of bioinformatic tools to insure a pertinent interpretation. Herein, we review the applications of pharmacoproteomics to the study of type 2 diabetes and to chemoresistance in different types of cancer and the current state of this technology in these pathologies. We also suggest a number of bioinformatic solutions for proteomic data management.

The human anti-thyroid peroxidase autoantibody repertoire in Graves' and Hashimoto's autoimmune thyroid diseases.

Human anti-thyroid peroxidase (TPO) autoantibodies (aAb) are generated during autoimmune thyroid diseases (AITD). Within recent years, increasing knowledge of the TPO-specific aAb repertoire, gained mainly by the use of combinatorial library methodology, has led to the cloning and sequencing of around 180 human anti-TPO aAb. Analysis of the immunoglobulin (Ig) variable (V) genes encoding the TPO aAb in the ImMunoGeneTics database (IMGT) (http://imgt.cines.fr) reveals major features of the TPO-directed aAb repertoire during AITD. Heavy chain VH domains of TPO-specific aAb from Graves' disease patients preferentially use D proximal IGHV1 genes, whereas those from Hashimoto's thyroiditis are characterized more frequently by IGHV3 genes, mainly located in the middle of the IGH locus. A large proportion of the anti-TPO heavy chain VH domains is obtained following a VDJ recombination process that uses inverted D genes. J distal IGKV1 and IGLV1 genes are predominantly used in TPO aAb. In contrast to the numerous somatic hypermutations in the TPO-specific heavy chains, there is only limited amino acid replacement in most of the TPO-specific light chains, particularly in those encoded by J proximal IGLV or IGKV genes, suggesting that a defect in receptor editing can occur during aAb generation in AITD. Among the predominant IGHV1 or IGKV1 TPO aAb, conserved somatic mutations are the hallmark of the TPO aAb repertoire. The aim of this review is to provide new insights into aAb generation against TPO, a major autoantigen involved in AITD.